Process for preparing rac-bicalutamide and its intermediates

ABSTRACT

The present invention relates to a new process for the synthesis of racemic and optically active bicalutamide starting from ethyl pyruvate and methyl methacrylate. The present invention discloses processes of preparing bicalutamide intermediates including ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionate, 1,2-epoxy-2-methyl propionate and 2-hydrox-2-methyl-3-(4-fluorophenylthio) propionic acid. The present invention further discloses micronized rac-bicalutamide and the preparation thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefits under 35 U.S.C. § 119(e) ofProvisional Application Serial No. 60/298,009, filed Jun. 13, 2001 andNo. 60/371,069, filed on Apr. 9, 2002, the disclosures of which areincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to process for preparing rac-bicalutamideand its intermediates. The prevent invention also relates to micronizedrac-bicalutamides and their preparations thereof.

BACKGROUND OF THE INVENTION

Bicalutamide is also known asN-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-sulfonyl]-2-hydroxy-2-methyl-propionamideand has the following chemical formula.

Bicalutamide is an acylanilid that has anti-androgen activity. It isknown to selectively decrease the testosterone level without influencingthe regulation mechanisms of the hypothalamus.

The international patent No. WO 93/19770 describes both R-(−) enantiomerand S-(+) enantiomer for bicalutamide, of which the R-(−) isomer isreported to be more active and possesses lesser side-effects (e.g.,headache, gynecomistia and giddiness) when used in therapy treatment.

U.S. Pat. No. 4,636,505 describes processes for preparing acylanilides.

The international Pat. No. WO 01/00608 describes a process for racemicand optically pureN-[4-cyano-3-trifluoromethylphenyl]-3-[4-fluorophenyl-sulfonyl]-2-hydroxy-2-methyl-propionamide.The process involves multiple steps including at least reacting withthionyl choride; hydrolyzing under aqueous basic conditions;sulfonylating with sulfonyl halogenide; and oxidizing with inorganicperoxy salt, or m-chloroperbenzoic acid (MCPBA) or aqueous hydrogenperoxide. However, the synthetic pathways involve the use of substrates(such as sodium hydride) that are dangerously explosive in nature.

There is a constant need to improve the synthesis process forbicalutamide which are economical and environmental safe and feasible.

We have now found a simpler method of preparing bicalutamide and itsintermediates without using dangerous oxidizing compounds such asm-chloroperbenzoic acid.

OBJECTS AND SUMMARY OF THE INVENTION

The present invention provides new synthetic pathways for preparingrac-bicalutamide and its intermediates.

According to one object, the present invention is directed to arac-bicalutamide intermediate having a chemical formula of [X], whichrepresents a stable organo lithium salt of 4-fluorophenyl methylsulfone.

According to another object, the present invention is directed to aprocess of preparing [X], comprising the step of reacting 4-fluorophenylmethyl sulfone with butyl lithium to form the organo lithium salt of4-fluorophenyl methyl sulfone.

According to another object, the present invention provides a novelprocess for preparing rac-ethyl 1-[2-{4-fluorophenyl sulfone}]-2-hydroxypropionic acid, comprising the step of reacting the organo lithium saltof 4-fluorophenyl methyl sulfone with ethyl pyruvate.

According to another object, the present invention is directed to arac-bicalutamide intermediate having a chemical formula of [Y], whichrepresents a stable lithium salt of 5-amino-2-cyano-benzotrifluoride.

According to another object, the present invention provides a precessfor preparing [Y], comprising the step of reacting5-amino-2-cyano-benzotrifluoride with butyl lithium to form the lithiumsalt of 5-amino-cyano-benzotrifluoride.

According to another object, the present invention provides a processfor preparing rac-bicalutamide, comprising the step of reacting [Y] withrac-ethyl 1-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionic acid.

According to another object, the present invention provides a processfor preparing rac-ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionicacid, comprising the steps of:

1) mixing 4-fluorophenyl methyl sulfone with butyl lithium to obtain anintermediate having a chemical structure [X];

2) adding ethyl pyruvate; and

3) recovering rac-ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionicacid.

Preferably, 1,4 diazabicyclo[2.2.2]octane in tetrahydrofuran is used asa stablizied agent in step 1.

According to another object, the present invention provides a processfor preparign rac-bicalutamide comprising the steps of:

1) mixing 5-amino-2-cyano-benzotrifluoride and butyl lithium to obtain alithium salt of 5-amino-2-cyano-benzotrifloride;

2) adding rac-ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionicacid; and

3) recovering rac-bicalutamide.

Preferably, the step 1) is occurred in the presence of 1,4diazabicyclo[2.2.2]octane in tetrahydrofuran.

According to one object, the present invention provides a novel processof preparing micronized forms of rac-bicalutamide.

According to another object, the present invention provides a synthesisprocess of preparing rac-bicalutamide with a particle size in which themean particle size enhances the rate of dissolution and thereproducibility of dissolution. The present invention providesrac-bicalutamide in which the mean particle size imparts an improved andstable dissolution profile.

According to another object, the present invention providesrac-bicalutamide formulations containing rac-bicalutamide havingrelatively small particles, and corresponding large surface area.

According to another object, the present invention providesrac-bicalutamide with a particle size which enhances the rate ofdissolution and the reproducibility of the rate of dissolution.

According to another object, the present invention providesrac-bicalutamide in which the mean particle size imparts an improved andstable dissolution profile.

According to another object, the present invention providesrac-bicalutamide and formulations containing rac-bicalutamide having amean particle diameter of less than 200 μm.

According to another object, the present invention provides a processfor preparing micronized rac-bicalutamide.

According to another object, the present invention providespharmaceutical compositions comprising micronized rac-bicalutamide.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the reaction pathway of rac-bicalutamide synthesisstarting from ethyl pyruvate.

FIG. 2 depicts the reaction pathway of rac-bicalutamide synthesisstarting from methyl methacrylate.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, rac-bicalutamide refers to both the R-(−) enantiomer andS-(+) enantiomer of bicalutamide. Rac-bicalutamide is the racemic andoptically pure R-(−) and S-(+) isomers ofN-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-sulfonyl]-2-hydroxy-2-methyl-propionamide.It is to be understood that this invention encompasses the racemic formof bicalutamide and any optically-active form which possessesanti-androgenic activity. It is a matter of common general knowledge howa racemic compound may be resolved into its optically-active forms andhow any anti-androgenic activity present in any of these forms may bedetermined. One skilled in the art will appreciate that the separationof optical isomers can be achieved by conventional resolution; such asfractional crystallization or flash-chromatography.

As used herein, the term “micronized” refers to particles having a meanparticle diameter of less than about 200 μm.

As used herein, the term “μm” refers to “micrometer” which is 1×10⁻⁶meter.

The following abbreviations are used herein: DCM is dichloromethane. THFis tetrahydrofuran. DABCO is 1,4 dizazbicyl[2.2.2]octane. ACB is5-amino-2-cyano-benzotrofluoride. BCL is rac-bicalutamide. 4-FPMS is4-fluorophenyl methyl sulfone.

The present invention provides a novel process for preparingrac-bicalutamide from ethyl pyruvate and 4-fluoropheynl methyl sulfonevia the formation of an intermediate with chemical formula of [X].

The present invention further provides a novel process for preparingrac-bicalutamide from 4-fluorophenyl methyl sulfone. Butyl lithiumreacts with 4-fluorophenyl methyl sulfone with a base to form an organolithium the intermediate (i.e., with chemical formula of [X]),optionally in the presence of anion stabilizer such as DABCO. The baserefers to strong bases such as lithium diisopropyl amid (LDA) or itsderivatives. This reaction is preferably carried out in an inert organicsolvent, for example tetrahydrofuran or diethyl ether. Most preferablesolvent is tetrahydrofuran. The reaction is preferably carried out at alow temperature, for example −40° C. to 10° C. Most preferabletemperature is between −2° C. and 2° C.

FIG. 1 illustrates the schematic process for preparing rac-bicalutamidefrom ethyl pyruvate and 4-fluorophenyl methyl sulfone. The intermediatewith general chemical formula of [X] reacts with ethyl pyruvate to formethyl-[2-4-{4-fluorophenyl sulfone}]-2-hydroxy propionate. This reactionis preferably carried out in an inert organic solvent, for exampletetrahydrofuran or diethyl ether. Most preferable solvent istetrahydrofuran. The reaction is preferably carried out at a lowtemperature, for example −60° C. to −100° C. Most preferable temperatureis −60° C.

The present invention provides a process of preparing rac-bicalutamidefrom 5-amino-2-cyano-benzotrifluoride. Butyl lithium reacts with5-amino-2-cyano-benzotriflouride with a base to form an organo lithiumthe intermediate (i.e., with chemical formula of [Y]), optionally in thepresence of anion stabilizer such as DABCO. The base refers to strongbases such as lithium diisopropyl amid (LDA) or its derivatives. Thisreaction is preferably carried out in an inert organic solvent, forexample tetrahydrofuran or diethyl ether. Most preferable solvent istetrahydrofuran. The reaction is preferably carried out at a lowtemperature, for example −40° C. to 10° C. Most preferable temperatureis between −2° C. and 2° C.

The present invention provides a process of preparing rac-bicalutamidefrom 5-amino-2-cyano-benzotrifluoride via intermediate with chemicalformula of [Y]. Intermediate with chemcial formula [Y] thus formedreacts with rac-ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionateto form rac-bicalutamide. This reaction is preferably carried out in aninert organic solvent, for example tetrahydrofuran or diethyl ether.Most preferable solvent is tetrahydrofuran. The reaction is preferablycarried out at a low temperature, for example −60° C. to −100° C. Mostpreferable temperature is −60° C.

The detailed procedures of preparing rac-ethyl-[2-{4-fluorophenylsulfone}]-2-hydroxy propionic acid from ethyl pyruvate and4-fluorophenyl methyl sulfone as well as rac-bicalutamide fromrac-ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionic acid and5-amino-2-cyano-benzotrifluoride are illustrated in FIG. 1.

The process according to our invention is described in detail by thefollowing, but not limiting, examples.

EXAMPLE 1 Preparation of rac-Ethyl-[2-{4-FluorophenylSulfone}]-2-Hydroxy Propionate

4-Fluorophenyl methyl sulfone (4-FPMS) (5 grams, 27.8 mmol) and 1,4diazabicyclo[2.2.2]octane (DABCO) (3.2 grams, 28.5 mmol) were dissolvedin tetrahydrofuran (THF) and cooled in dry-ice acetone bath to about −2°C.

A 2.5 M solution of butyl lithium in hexanes (14.5 mL, 36.2 mmol) wasadded to the cold THF solution dropwise via a syringe while keeping thetemperature between about −2° C. to about 2° C. After addition wascompleted the stirring was continued for about 1 hour while maintainingthe temperature at about −2° C. Then, the temperature was lowered toabout −65° C. and a solution of ethyl pyruvate (3.67 grams, 31.6 mmol)in THF (30 mL) was added dropwise.

After addition was completed, the stirring was continued for an hour attemperatures between about −65° C. and about −30° C. and then followedby an addition of 2N HCl (30 mL) dropwise to the reaction mixture atabout −30° C. The reaction was allowed to warm-up to room temperatureand the mixture was evaporated in vacuo on a rotary evaporator to removeTHF and ethanol.

The residual material was extracted with diethyl ether (3×100 mL). Thecombined ether extracts were dried over Na₂SO₄, filtered and thefiltrate was completely evaporated to give a crude oil.

The product was purified by column chromatography on silica gel viaeluting with dichloromethane (DCM) to give rac-ethyl-[2-{4-fluorophenylsulfone}]-2-hydroxy propionate as colorless oil.

The purified product was characterized by a ¹H NMR (500 MHz, CDCl₃):7.92 (m, 2H), 7.22 (m, 2H), 4.29 (m, 2H, OCH₂), 3.77 (d, J=15 Hz,1H,CH_(2α)), 3.68 (bs, 1H, OH), 3.55 (d, J=15 Hz, 1H, CH_(2β)), 1.45 (s,3H, Me), 1.35 (t, J=7 Hz, 3H, OCH₂CH₃).

The purified product was further characterized by a ¹³C NMR (125.7 MHz,CDCl₃): 174.7 ppm (CO_(ester)), 166.4 (C-4′, J_(C-F)=258 Hz), 137.5((c-1′), 131.7 (C-2′,6′, J_(C-F)=9 Hz), 117.0 (C-3′,5′, J_(C-F)=21.6Hz), 72.9 (C_(quat)), 64.6 (CH₂), 63.6 (OCH₂), 27.9 (CH₃), 14.7(OCH₂CH₃).

The purified product was further characterized by HPLC(acetonitrile:water 1:1 with 0.01% TFA): 5.4 mins.

EXAMPLE 2 Preparation ofrac-N-[4-Cyano-3-Trifluoromethyl-Phenyl]-3-[4-FluorophenylSulfonyl]-2-Hydroxy-2-Methyl-Propionamide

5-Amino-2-cyano-benzotrifluoride (ACB) (0.27 grams, 1.45 mmol) and 1,4diazabicyclo[2.2.2]octane (DABCO) (0.32 grams, 2.85 mmol) were dissolvedin tetrahydrofuran (THF) (30 mL) and cooled in dry-ice acetone bath toabout −2° C.

A 2.5M solution of butyl lithium in hexanes (2 mL, 5 mmol) was added tothe cold THF solution dropwise via a syringe while keeping thetemperature between about −2 to about 2° C. After addition wascompleted, the stirring was continued for 1 hour while maintaining thetemperature at about −2° C. The temperature was then lowered to about−65° C. and a solution of rac-Ethyl-[2-{4-fluorophenylsulfone}]-2-hydroxy propionate (0.34 grams, 1.17 mmol) in THF (20 mL)was added dropwise.

After addition was completed, the stirring was continued for an hour attemperatures between about −65° C. and about −30° C. after which 2N HCl(30 mL) was added dropwise to the reaction mixture at about −30° C. Thereaction was allowed to warm-up to room temperature and the mixture wasevaporated in vacuo on a rotary evaporator to remove THF and ethanol.

The residual material was extracted with diethyl ether (3×100 mL). Thecombined ether extracts were dried over Na₂SO₄, filtered and thefiltrate was completely evaporated to give a crude oil.

The product was purified by column chromatography on silica gel elutingwith ethyl acetate-petroleum ether to giverac-N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenylsulfonyl]-2-hydroxy-2-methyl-propionamide in about 40% yield, as a paleyellow solid.

The present invention further provides a novel process for preparingrac-bicalutamide from methyl methacrylate. FIG. 2 illustrates theschematic process for preparing rac-bicalutamide from methylmethacrylate.

According to FIG. 2, the starting material was methyl methacrylate,which can usually be converted into the epoxide only under harshconditions (i.e. with peracetic acid in ethyl acetate at 75° C.[J.A.Chem., 81, 680 (1959)], or with 90% hydrogenperoxide-trifluoroacetic anhydride at 40° C. [J.Am.Chem., 77, 89(1955)], or with MCPBA in dichloromethane at 0° C. in low yield[J.Med.Chem., 29, 2184 (1986)]. The epoxidation under these conditionscan be explosive. The present invention describes this oxidation usingOxone®.

The methyl 2-methyl-oxirane-carboxylate of formula (1), which wasobtained by epoxidation, was reacted with 4-fluorothiophenol [formula(2)] in the presence of sodium hydride under the conditions listed inScheme-2. The obtained methyl2-hydroxy-2-methyl-3-(4-fluorophenylthio)-propionate of formula (3) washydrolyzed with potassium hydroxide in aqueous ethanol over a period of22 hours to yield the2-hydroxy-2-methyl-3-(4-fluorophenylthio)-propionic acid of formula (4),which was converted into the acid chloride of formula (5) with thionylchloride in dimethyl acetamide at −15° C.

The obtained acid chloride was reacted with4-amino-2-trifluoromethyl-benzonitrile in dimethylacetamide at −15° C.to yield the thioether derivative of formula (6). The oxidation of thethioether derivative was carried out by known method withm-chloroperbenzoic acid in dichloromethane to yield the final product,bicalutamide, of formula (7).

The process according to our invention is described in detail by thefollowing, but not limiting, examples.

EXAMPLE 3 Preparation of Methyl 1,2-Epoxy-2-Methyl-Propionate

In a 3 L four-neck round bottom flask, Oxone® (50% KHSO₅, 227 grams,0.75 mol) was dissolved in water (1 L) and 10 M KOH was added to adjustthe pH to ˜6 (˜53 mL). Then, methyl methacrylate (13 mL, 0.122 mol) inmethanol was added (50 mL) followed by 360 mL of water.

The solution was stirred at room temperature and the pH was continuouslyadjusted to pH=6 with 1M KOH (˜270 mL). After 6 hr the reaction wasstirred over night. Then, 2N HCl was added (100 mL, pH=3) and the entireaqueous solution was extracted with DCM (3×150 mL) for each 400 mLreaction solution. The combined DCM extracts were washed with saturatedsodium sulfite solution followed by saturated sodium bicarbonatesolution.

After drying and filtartion, DCM was removed by evaporation and theunreacted methyl methacrylate was distilled out. The residue containedthe product as an oily material.

GC: (>97%, 1.45 min); yield: 66%; ¹H NMR (500 MHz, CDCL₃; □ ppm 3.72(s,3H, Me), 3.07 (dd, J=6 Hz, J=16 Hz, 1H, H_(□)), 2.73 (d, J=6 Hz, 1H,H_(□)), 1.55 (s, Me); ¹³C-NMR (125.7 MHz, CDCL₃; □ ppm): 172(CO_(ester)), 54.3 (CH₂), 53.6 (C_(quat)), 53.2 (Me_(ester)), 18 (Me).

EXAMPLE 4 Preparation of 2-Hydroxy-2-Methyl-3-(4-Fluorophenylthio)Propionic Acid

To a solution of 4-fluorothiophenol (1 mL) in MeOH (32 mL) was addeddropwise 2N NaOH_(aq) (16 mL) under N₂, while the temperature was keptat 25° C. during the addition period. When addition was completed, thereaction mixture was stirred at room temperature for a further 90 min.

A solution of methyl-1,2-epoxy-2-methyl propionate (1.2 gram) in MeOH(20 mL) was then added dropwise at room temperature. When addition wascompleted, the reaction mixture was stirred over night at ambienttemperature. To the reaction mixture 2N HCl (20 mL) was added followedby ethyl acetate (60 mL). The organic phase was separated. The aqueousphase (pH˜2) was extracted with 60 mL of chloroform and then discarded.The ethyl acetate and chloroform extracts were combined.

After drying (MgSO₄) and filtration, the two organic solvents wereevaoprated to leave an oily product which solidified upon standing atroom temperature.

Purity: 75% (according to GC); Yield: 66%. GCMS: 230 m/z (13%); M.p.:69.1-72.7° C.; ¹H NMR (500 MHz, CDCL₃; □ ppm 7.43 (m, 2H, H-2′,6′), 6.96(m, 2H, H-3′,5′), 3.39 (d, J=14 Hz, 1H, H_(□)), 3.17 (d, J=14 Hz, 1H,H_(□)), 1.53 (s, Me); ¹³C-NMR (125.7 MHz, CDCL₃; □ ppm): 180.4(CO_(acid)), 162.6 (d, J_(C-F)=248 Hz, C-4′), 134.3 (d, J_(C-F)7.5 Hz,C-2′,6′), 130.8 (d, J_(C-F)=3.2 Hz, C-1′), 116.5 (d, J_(C-F)=21.6 Hz,C-3′,5′), 7.52 (C_(quat)), 53.3 (Me_(ester)), 46.4 (CH₂), 26.0 (Me).

Micronized Rac-Bicalutamide

The Particle Size Distribution (PSD) of rac-bicalutamide may be used todetermine the available surface area for the drug dissolution. Often, itis observed that the available surface area for drug dissolutioncorrelates to both (a) the rate of dissolution and solubility where agreat surface area enhances the solubility of a drug; and (b) enhancesthe rate of dissolution of a drug. The rate of dissolution of a drugeffects the drug's bioavailability. Thus, the PSD of rac-bicalutamide,and in particular, the meagrn particle diameter, are importantparameters to characterize and predict the bioavailibility ofrac-bicalutamide.

The present invention provides rac-bicalutamide formulations containingrac-bicalutamide having relative small particles and correspondingrelatively large surface area.

The present invention provides rac-bicalutamide formulations containingrac-bicalutamide having a mean particle diameter of less than 200 μm,preferably the mean particle diameter is less than 100 μm, morepreferably the mean particle diameter is less than 20 μm, and mostpreferably the mean particle size is about 10 μm.

The present invention provides rac-bicalutamide having a mean particlediameter of between about 200 μm and about 10 μm. In one embodiment ofthe invention, rac-bicalutamide has a mean diameter of about 4.2 μm,more preferably a mean diameter of 4.0 μm.

The present invention also provides process for preparing micronizedrac-bicalutamide. By the methods of the present invention,rac-bicalutamide, which is prepared by methods known in the art, isseparated by sieves to produce rac-bicalutamide wherein 50% has a meanparticle diameter of below about 250 μm and about 80% has a meanparticle diameter of below about 500 μm. The sieved rac-bicalutamide isthen micronized by methods known in the art, e.g., in a micronizer, toyield rac-bicalutamide wherein 100% of rac-bicalutamide has a meanparticle size of less than about 45 μm, preferably 99% of therac-bicalutamide has a mean particle size of less than about 45 μm, morepreferably, 93% of the rac-bicalutamide has a mean particle size of lessthan about 7.5 μm, more preferably the rac-bicalutamide isolated has amean particle diameter of less than about 10 μm.

Micronized particles of rac-bicalutamide can be obtained by the use ofconventional micronizing techniques after sieving to providerac-bicalutamide wherein about 50% has a particle size of less thanabout 250 μm and about 80% has a particle size of less than 500 μm. Bythe methods of the present invention, the rac-bicalutamide where about50% has a particle size less than 500 μm and about 80% has a particlesize below about 500 μm, is micronized to the desired particle sizerange by methods known in the art, for example, using a ball mill,ultraonic means, fluid energy attrition mills, or using a jet mill, orother suitable means as disclosed in Pharmaceutical Dosage Forms:Tablets, Vol. 2, 2^(nd) Ed., Lieberman et al. Ed., Marcel Dekker, Inc.New York (1990) p.107-200, the content of which is incorporated byreference herein.

The present invention provides micronized rac-bicalutamide aspharmaceutical compositions that are particularly useful for itsanti-androgen activity. Such compositions comprise micronizedrac-bicalutamide with pharmaceutically acceptable carriers and/orexcipients known to one of skilled in the art.

Preferably, these compositions are prepared as medicaments to beadministered orally or intravenously. Suitable forms for oraladministration niclude tablets, compressed or coated pills, dragees,sachets, hard or gelatin capsules, sub-lingual tablets, syrups andsuspensions. While one of ordinary skill in the art will understand thatdosages will vary according to the indication, age and severity of thedisease of the patent etc., generally micronized rac-bicalutamide of thepresent invention will be administered at a daily dosage of about 2 mgto about 200 mg per day, and preferably about 5 mg to about 100 mg perday.

What is claimed is:
 1. A rac-bicalutamide intermediate having thechemical structure of [X], wherein [X] is a stable organo lithium saltof 4-fluorophenyl methyl sulfone.
 2. A process of preparingethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionate, comprises thesteps of: a) reacting a lithium salt of 4-fluorophenyl methyl sulfone inan organic solvent with ethyl pyruvate; and b) recoveringethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionate.
 3. The processaccording to claim 2, wherein the organic solvent is tetrahydrofuran. 4.The process according to claim 2, wherein the ethyl pyruvate is added tothe mixture at a temperature of about −65° C.
 5. The process accordingto claim 2, wherein the recovering step comprises evaporating themixture containing ethyl pyruvate.
 6. The process according to claim 2,wherein the recovering step further comprises separating theethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionate.
 7. The processof claim 2, wherein the process preparing lithium salt of 4-fluorophenylmethyl sulfone, comprises the steps of: a) dissolving 4-fluorophenylmethyl sulfone in an organic solvent; and b) adding butyl lithium to thesolution, wherein butyl lithium reacts with 4-fluorophenyl methylsulfone to form.
 8. The process according to claim 7, wherein theorganic solvent is selected from the group consisting of tetrahydrofuranand diethyl ether.
 9. The process according to claim 7, wherein thereaction between butyl lithium with 4-fluorophenyl methyl sulfonateoccurs in the presence of an anion stabilizer.
 10. The process accordingto claim 9, wherein the anion stabilizer is 1,4diazabicylo[2.2.2]octane.
 11. The process according to claim 7, whereinthe reaction between butyl lithium 4-fluorophenyl methyl sulfone occursin a temperature range between about −40° C. to about +2° C.
 12. Theprocess according to claim 7, wherein the reaction between butyl lithiumwith 4-fluorophenyl methyl sulfone occurs in a temperature range betweenabout −2° C. and about +2° C.